Buprenorphine dosing regimens

ABSTRACT

The disclosure provides a dosage regimen using sustained-release buprenorphine formulations to produce therapeutic levels of buprenorphine in patients for the treatment of pain or opioid use disorders.

RELATED APPLICATIONS

This application is a Section 371 U.S. national phase application of PCTApplication No. PCT/IB2015/002269 filed Nov. 6, 2015, which claimspriority to U.S. Application No. 62/076,854 filed Nov. 7, 2014, U.S.Application No. 62/100,391 filed Jan. 6, 2015; U.S. Application No.62/112,546 filed Feb. 5, 2015, and U.S. Application No. 62/199,778 filedJul. 31, 2015, the disclosures of which are incorporated by referenceherein in their entirety.

BACKGROUND

The disclosure is directed to dosing regimens for sustained-releasebuprenorphine formulations that provide sustained therapeutic levels ofbuprenorphine and μ-opioid receptor occupancy for the treatment of painand opioid use disorders.

Opioid addiction is a neurobehavioral syndrome characterized by therepeated, compulsive seeking and use of an opioid despite adversesocial, psychological, and/or physical consequences. Opioid addiction isa problem with high costs to individuals, families, and society. The useof prescription opioids has tremendously increased in the past decade inthe United States (from 174 million in 2000 to 257 million in 2009) dueto the widespread availability and variety of prescription opioidproducts, and changes in treatment paradigms. Opioid abuse, addiction,overdose, and other health and social consequences of opioid misuse aretaking a rapidly growing toll on individuals and institutions in theUnited States. It is estimated that 2.2 to 2.4 million individualsinitiate non-medical use of opioids in the United States each year andnon-medical opioid use now exceeds use of many conventional streetdrugs, including cocaine and heroin. Overdose deaths from prescriptiondrugs have exceeded those from street drugs since 2002 and havesurpassed traffic accidents as a cause of accidental death. In 2011,over 1,252,500 of 2.5 million emergency department (ED) visitsassociated with drug abuse or addiction involved illicit drugs,including 258,482 ED visits related to heroin and about 420,040 EDvisits related to narcotic pain relievers.

Opioid receptors are located in both the central nervous system (CNS)and the periphery. In the CNS, they are found in high concentrations inthe limbic system and the spinal cord. The natural ligands for theopioid receptors are a group of neuropeptides known as endorphins.Opioid analgesics mimic the action of these natural ligands, but have amore prolonged action as they are not subject to rapid local metabolism.Three major opioid receptor subclasses have been identified: μ-, κ-, andδ-. Buprenorphine is a partial opioid agonist at the μ-opioid receptor,with antagonist properties at the κ-receptor. In contrast to a fullagonist, buprenorphine at the μ-receptor has less maximal euphoriceffect, and a ceiling on its respiratory depressant effects. By bindingto μ-opioid receptors in the brain, buprenorphine reduces craving foropioids and opiate withdrawal symptoms, minimizing the need ofopioid-dependent patients to use illicit opiate drugs. For themaintenance treatment of opioid dependence, SUBUTEX® (buprenorphine;Indivior PLC), SUBOXONE® tablets (buprenorphine/naloxone; Indivior PLC),or SUBOXONE® film (buprenorphine/naloxone; Indivior PLC) may be given asa single daily dose ranging from 4 to 24 mg per day, with therecommended dosage being 16 mg buprenorphine per day.

A major issue in the pharmacological treatment of opioid dependence isthe high rate of non-adherence. Currently, there is no approvedparenterally-administered, sustained-release buprenorphine productindicated for the treatment of opioid dependence. Such a product couldoffer advantages over existing buprenorphine pharmacotherapy byimproving patient compliance and reducing diversion, abuse, andunintended exposure, particularly regarding children.

To this end, the present disclosure is directed to dosing regimens forsustained-release formulations of buprenorphine that provide, amongother benefits, optimal buprenorphine dosages, therapeutic buprenorphineconcentrations, and therapeutic μ-opioid receptor occupancy for thetreatment of opioid dependence or pain.

SUMMARY

The disclosure provides dosing regimens for treating opioid dependenceor pain in a human in need thereof including the steps of: (a)administering a first composition including a dose of buprenorphine tothe human once per month by injection for one month, two months, orthree months; and thereafter (b) administering a second compositionincluding a dose of buprenorphine to the human once per month byinjection beginning with the second month, third month, or fourth monthof administration, respectively, and for each month thereafter; to treatthe opioid dependence or pain; wherein the amount of buprenorphine inthe first composition is greater than the amount of buprenorphine in thesecond composition. In embodiments, the dosing regimen is for treatingopioid dependence. In embodiments, the dosing regimen is for treatingpain.

A comprehensive model-based approach was developed to describe thepopulation pharmacokinetics of sustained-release buprenorphineformulations in opioid-dependent subjects and to define therelationships between buprenorphine plasma concentrations with μ-opioidreceptor occupancy (μORO) and clinical efficacy. The results of theseanalyses provide new insight into the long-acting pharmacokinetic andpharmacokinetic/μORO profile of sustained-release buprenorphineformulations. These findings indicated that sustained-releasebuprenorphine formulations can become an effective treatment of opioiddependence by addressing the compliance, reducing diversion, abuse, andunintended exposure associated with conventional treatments. Thedisclosure empirically combined clinical molecular neuroimaging, andplasma concentration and pharmacodynamic data to predict an effectivedosing regimens for sustained-release buprenorphine formulations.

The disclosure provides a methodological approach to exploit all theinformation available, using comprehensive modeling approach tointegrate and learn from the data generated in different studies thepharmacokinetic and PK/PD characteristics of sustained-releasebuprenorphine formulations. This learning has been subsequently appliedto address relevant questions for the clinical development ofsustained-release buprenorphine formulations.

This strategy was implemented by initially defining a populationpharmacokinetic model of buprenorphine and norbuprenorphine using dataobtained in 36 opioid-dependent subjects who received Formulation D (asdescribed herein) with 50 mg, 100 mg, or 200 mg of buprenorphine base. Apopulation pharmacokinetic/μORO model was developed using data(buprenorphine pharmacokinetic and μORO) collected in 15heroin-dependent subjects (5 receiving buprenorphine daily tablet dosesof 32 mg, 16 mg, 2 mg, or placebo and 10 receiving buprenorphine dailytablet dose of 16 mg). The results of the buprenorphine populationpharmacokinetic analysis were combined with results of the populationpharmacokinetic/μORO analysis to estimate the expected μORO afterrepeated subcutaneous injections of different doses of Formulation Dadministered once a month. As expected, blockade of hydromorphoneagonist effects, withdrawal symptoms and plasma buprenorphineconcentrations were correlated with μORO.

Norbuprenorphine is a major metabolite of buprenorphine and potentagonist of μ, δ, and κ opioid receptors. However, while norbuprenorphineis able to bind the μ-opioid receptors, it does not appreciabledistribute to the CNS and would not affect the pharmacodynamicendpoints. The reasons why norbuprenorphine was included in the model isthat it binds to peripheral μ-opioid receptors, with potentialinvolvement in safety, and is important to the overall clinicaldevelopment plan. In any case, considering that the norbuprenorphineconcentrations were available, it was a reasonable strategy to evaluatethese data in a comprehensive model for a better characterization andunderstanding of buprenorphine pharmacokinetics.

Analysis of the pharmacokinetic profile of Formulation D revealed acomplex absorption profile, presenting double peaks and a prolongedplasma terminal half-life. These distinguishing features of thepharmacokinetics of Formulation D required the development of a complexpharmacokinetic model accounting for these dual absorption processes: afirst absorption process that was associated with an initial rapiddelivery from the subcutaneous injection site, and a second absorptionprocess that was associated with a slow release from thesustained-release formulation into the systemic circulation. The meantransit time associated with the slow release from the sustained-releaseformulations could be estimated at 10 weeks, which is the likely reasonfor the curvilinear shape of the plasma concentration-time profile.

The buprenorphine plasma exposure increased proportionally with dose.The established model was stable and described the data well. Thecovariate analysis was unable to detect any relevant impact of thedemographic characteristics of the subjects enrolled in the trial,probably due to the limited sample size.

The clinical efficacy of opioid medication assisted therapy for thetreatment of opioid dependence is believed to result from a medication'sability to alleviate withdrawal symptoms, and bind μ-opioid receptorsresulting in blockade of subjective agonist effects. Greenwald et al,Biol Psychiatry, 61:101-110 (2007) suggests that the threshold forsuppressing withdrawal and the blockade of agonist symptom effects isbetween 50-60% buprenorphine μORO while additional benefit and clinicalefficacy was observed at 70% μORO. As a result from these findings, doseselection criterion was based on the selection of a dose appropriate toreaching and maintaining a μORO greater than 70% after multiple doses.

The population pharmacokinetic/μORO model fully characterized therelationship between buprenorphine plasma levels and μORO. Therelationship between buprenorphine plasma concentration and μORO wasbest described by an E_(max) model with EC₅₀ of 0.67 ng/mL and E_(max)of 91%. The E_(max) model showed a linear relationship between μORO upto the desired 70% receptor occupancy and buprenorphine concentrationsup to about 2 ng/mL. At buprenorphine concentrations greater than 2ng/mL, saturation occurred on μORO where 4.5-fold increase in observedbuprenorphine concentrations resulted in observed μORO between 70% andless than 90%. Thus, once μORO is saturated, increasing doses are notexpected to exert any appreciable effect. A linear correlation wasestablished between buprenorphine clinical efficacy (withdrawalsuppression and blockade of hydromorphone agonist subjective effects)and μORO. Trial simulation indicated that ≥70% receptor occupancy may beachieved after multiple doses of 200 mg Formulation D once every 28days.

DETAILED DESCRIPTION

In one embodiment, the disclosure provides methods of treating opioiddependence or pain in a human in need thereof comprising the steps of(a) administering a first composition comprising a dose of buprenorphineto the human once per month by injection for one month; and thereafter(b) administering a second composition comprising a dose ofbuprenorphine to the human once per month by injection beginning withthe second month of administration and for each month thereafter; totreat the opioid dependence or pain; wherein the amount of buprenorphinein the first composition is greater than the amount of buprenorphine inthe second composition.

In one embodiment, the disclosure provides methods of treating opioiddependence or pain in a human in need thereof comprising the steps of(a) administering a first composition comprising a dose of buprenorphineto the human once per month by injection for two months; and thereafter(b) administering a second composition comprising a dose ofbuprenorphine to the human once per month by injection beginning withthe third month of administration and for each month thereafter; totreat the opioid dependence or pain; wherein the amount of buprenorphinein the first composition is greater than the amount of buprenorphine inthe second composition.

In one embodiment, the disclosure provides methods of treating opioiddependence or pain in a human in need thereof comprising the steps of(a) administering a first composition comprising a dose of buprenorphineto the human once per month by injection for three months; andthereafter (b) administering a second composition comprising a dose ofbuprenorphine to the human once per month by injection beginning withthe fourth month of administration and for each month thereafter; totreat the opioid dependence or pain; wherein the amount of buprenorphinein the first composition is greater than the amount of buprenorphine inthe second composition.

As discussed herein, the amount of buprenorphine in the firstcomposition is greater than the amount of buprenorphine in the secondcomposition, where the second composition is administered as amaintenance therapy. Without intending to be bound by any theory, it hasbeen discovered that the first composition of buprenorphine administeredonce monthly for 1 to 3 months produces therapeutically effective levelsof buprenorphine and a sufficient μ-opioid receptor occupancy tosuppress opioid withdrawal signs and symptoms and block responses to aμ-opioid receptor agonist. Treatment for 1 to 3 months at the higherdose of buprenorphine allows the patients to have reduced cravings,physically and/or psychologically, for opioids. It has also beenunexpectedly discovered that once the patient has achieved thetherapeutically effective levels of buprenorphine and μ-opioid receptoroccupancy, including the reduced cravings for opioids, the secondcomposition comprising a lower dose of buprenorphine can be safely andeffectively administered once monthly to the human to maintain thetherapeutically effective treatment, without the lower dosage causing arelapse of opioid abuse by the patients. Advantages of administering thelower dosage include decreased side effects, and a step-wise approach toreducing the dosage to completely taper off treatment.

The term “buprenorphine” refers to buprenorphine in the form of a freebase and buprenorphine in the form of a pharmaceutically acceptablesalt. In the formulations described herein, buprenorphine is preferablyin the form of a free base.

The term “sustained-release buprenorphine formulation” refers to anyformulation comprising buprenorphine that can be administered byinjection and that can provide therapeutic levels of buprenorphine forat least 1 month. The injection can be a subcutaneous injection. Inother embodiments, the injection can be an intramuscular injection.

The “therapeutic levels” of buprenorphine provided by thesustained-release buprenorphine formulations are at therapeutic levelsthat are effective: (a) in the treatment of opioid use disorders, suchas opioid dependence; (b) in suppressing opioid withdrawal signs andsymptoms; and (c) in treating pain. Therapeutic levels can be measuredby the buprenorphine concentration (C_(ave)) in the human and/or theμ-opioid receptor occupancy in the patient, each of which are describedherein.

The term “one month” means 28 days to 31 days. In one embodiment, onemonth is 28 days. In one embodiment, one month is 30 days. In oneembodiment, one month is 31 days.

“Opioid use disorder” is defined in the Diagnostic and StatisticalManual for Mental Disorders, 5^(th) Edition (DSM-5) as a problematicpattern of opioid use leading to clinically significant impairment ordistress, as manifested by symptoms described in the DSM-5. As usedherein, the term “opioid use disorder” is synonymous with “opioiddependence,” “opioid addiction,” and “opioid abuse.”

The term “opioid withdrawal signs and symptoms” includes one or moresigns and symptoms associated with withdrawal from opioids. Such signsand symptoms can include one or more of the following: agitation,anxiety, muscle aches, increased tearing, insomnia, runny nose,sweating, yawning, abdominal cramping, diarrhea, dilated pupils, goosebumps, nausea, and vomiting. Opioid withdrawal symptoms can begin tooccur from a few hours to a few days after the last intake of an opioid,with the time being dependent on the opioid, the person's metabolism,and other factors.

In one embodiment, the sustained-release buprenorphine formulation is aformulation described in U.S. Pat. Nos. 8,921,387 or 8,975,270, thedisclosures of which are incorporated by reference herein in theirentirety. In one embodiment, the sustained-release buprenorphineformulation is a formulation described in US Publication No.2013/210853, the disclosures of which are incorporated by referenceherein in their entirety. In one embodiment, the sustained-releasebuprenorphine formulation is a formulation described in US PublicationNo. 2013/0202658, the disclosure of which is incorporated by referenceherein in its entirety. In one embodiment, the sustained-releasebuprenorphine formulation is a formulation described in U.S. Pat. No.8,236,755, the disclosure of which is incorporated by reference hereinin its entirety. In one embodiment, the sustained-release buprenorphineformulation is a formulation described in WO 2014/016428, the disclosureof which is incorporated by reference herein in its entirety.

In one embodiment, the sustained-release buprenorphine formulation isFormulation D. “Formulation D” is a flowable composition that comprises,consists essentially of, or consists of: (i) about 18 wt % buprenorphinein the form of the free base; (ii) about 32 wt % of a 50:50poly(DL-lactide-co-glycolide) copolymer having a carboxy terminal groupand having an average molecular weight of about 9,000 Daltons to about19,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.

In one embodiment, the sustained-release buprenorphine formulation isFormulation C. “Formulation C” is a flowable composition that comprises,consists essentially of, or consists of: (i) about 14 wt % to about 22wt % buprenorphine in the form of the free base; (ii) about 22 wt % toabout 42 wt % of a 50:50 to 80:20 poly(DL-lactide-co-glycolide)copolymer having an average molecular weight of about 5,000 Daltons toabout 30,000 Daltons; and (iii) about 40 wt % to about 60 wt % ofN-methyl-2-pyrrolidone.

In one embodiment, the sustained-release buprenorphine formulation isFormulation B. “Formulation B” is a flowable composition that comprises,consists essentially of, or consists of: (i) about 10 wt % to about 30wt % buprenorphine in the form of the free base; (ii) about 10 wt % toabout 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymerhaving an average molecular weight of about 5,000 Daltons to about40,000 Daltons; and (iii) about 30 wt % to about 70 wt % ofN-methyl-2-pyrrolidone.

In one embodiment, the sustained-release buprenorphine formulation isFormulation A. “Formulation A” is a flowable composition that comprises,consists essentially of, or consists of: (i) at least one biodegradablethermoplastic polymer; (ii) at least one organic liquid which comprisesan amide, an ester, a carbonate, a ketone, a lactam, an ether, asulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30wt % of buprenorphine in the form of a free base or pharmaceuticallyacceptable salt. In one embodiment, the buprenorphine is in the form ofa free base. In other embodiments, the buprenorphine is present in anamount from about 10 wt % to about 25 wt %; or in an amount from about15 wt % to about 20 wt %. In other embodiments, the organic liquid ispresent in an amount of about 30 wt % to about 70 wt %; or in an amountof about 40 wt % to about 60 wt %. In one embodiment, the organic liquidis N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethyleneglycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethylisosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate,monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerolformal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol,dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylenecarbonate, triacetin, dimethylsulfoxide, dimethylsulfone,epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of twoor more thereof. In other embodiments, the organic liquid isN-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, polyethylene glycol,ethanol, or a mixture of two or more thereof. In other embodiments, theorganic liquid is N-methyl-2-pyrrolidone. In other embodiments, thebiodegradable thermoplastic polymer is present in an amount of about 10wt % to about 60 wt %; or in an amount of about 20 wt % to about 40 wt%. In one embodiment, the polymer is a polylactide, a polyglycolide, apolycaprolactone, a copolymer thereof, a terpolymer thereof, anycombination thereof, or a mixture of two or more thereof. In oneembodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer.The polymer, such as the poly(DL-lactide-co-glycolide) copolymer, canhave an average molecular weight of about 1,000 Daltons to about 50,000Daltons; or from about 5,000 Daltons to about 40,000 Daltons; or fromabout 5,000 Daltons to about 30,000 Daltons; or from about 5,000 Daltonsto about 20,000 Daltons; or from about 10,000 Daltons to about 20,000Daltons. The poly(DL-lactide-co-glycolide) copolymer can be a 50:50 to95:5 poly(DL-lactide-co-glycolide) copolymer; or a 50:50 to 80:20poly(DL-lactide-co-glycolide) copolymer; or a 50:50poly(DL-lactide-co-glycolide) copolymer.

The phrase “average molecular weight” refers to the weight averagemolecular weight of a polymer as determined by gel permeationchromatography (also known as GPC or size exclusion chromatography(SEC)) using tetrahydrofuran (THF) as the solvent and using a molecularweight calibration curve using polystyrene standards.

In one embodiment of the methods described herein, the first compositioncomprises from about 25 mg to about 500 mg buprenorphine, and the secondcomposition comprises from about 1 mg to about 400 mg buprenorphine;provided that the amount of buprenorphine in the first composition isgreater than the amount of buprenorphine in the second composition. Inanother embodiment, the first composition comprises from about 150 mg toabout 500 mg buprenorphine, and the second composition comprises fromabout 10 mg to about 250 mg buprenorphine; provided that the amount ofbuprenorphine in the first composition is greater than the amount ofbuprenorphine in the second composition. In another embodiment, thefirst composition comprises from 176 mg to about 500 mg buprenorphine,and the second composition comprises from about 10 mg to 175 mgbuprenorphine. In another embodiment, the first composition comprisesfrom about 200 mg to about 400 mg buprenorphine, and the secondcomposition comprises from about 25 mg to about 160 mg buprenorphine. Inanother embodiment, the first composition comprises from about 250 mg toabout 350 mg buprenorphine, and the second composition comprises fromabout 50 mg to about 150 mg buprenorphine. In another embodiment, thefirst composition comprises from about 280 mg to about 320 mgbuprenorphine, and the second composition comprises from about 80 mg toabout 120 mg buprenorphine. In another embodiment, the first compositioncomprises about 300 mg buprenorphine, and the second compositioncomprises about 100 mg buprenorphine.

The therapeutically effective buprenorphine concentration produced bythe methods described herein is an average buprenorphine concentration(C_(ave)) of about 0.5 ng/mL to about 5 ng/mL in the human. In oneembodiment, average buprenorphine concentration (C_(ave)) is from about1 ng/mL to about 4.5 ng/mL in the human. In one embodiment, averagebuprenorphine concentration (C_(ave)) is from about 1.5 ng/mL to about 4ng/mL in the human. In one embodiment, average buprenorphineconcentration (C_(ave)) is from about 1.5 ng/mL to about 3.5 ng/mL inthe human. In one embodiment, average buprenorphine concentration(C_(ave)) is from about 2 ng/mL to about 4 ng/mL in the human. In oneembodiment, average buprenorphine concentration (C_(ave)) is from about2 ng/mL to about 3 ng/mL in the human. In one embodiment, averagebuprenorphine concentration (C_(ave)) is from about 2.5 ng/mL to about3.5 ng/mL in the human. In one embodiment, average buprenorphineconcentration (C_(ave)) is from about 3 ng/mL to about 4 ng/mL in thehuman. In one embodiment, average buprenorphine concentration (C_(ave))is from about 1.8 ng/mL to about 3.7 ng/mL in the human. In the methodsdescribed herein, the average buprenorphine concentration is achievedfrom one to four months after the first injection, when the injectionsare given on a monthly basis. In one embodiment, the averagebuprenorphine concentration is achieved from one to three months afterthe first injection, when the injections are given on a monthly basis.In one embodiment, the average buprenorphine concentration is achievedfrom one to two months after the first injection, when the injectionsare given on a monthly basis. In one embodiment, the averagebuprenorphine concentration is achieved within two months after thefirst injection, when the injections are given on a monthly basis. Inone embodiment, the average buprenorphine concentration is achievedwithin one month after the first injection.

The dosing regimen used in the methods described herein produces aμ-opioid receptor occupancy, as measured by the maximum effect model ofEquation 1 (described herein), greater than 60% in the human beingtreated. In one embodiment, the methods produce a μ-opioid receptoroccupancy (as measured by a maximum effect model of Equation 1) of atleast 70%. In one embodiment, the methods produce a μ-opioid receptoroccupancy (as measured by a maximum effect model of Equation 1) ofgreater than 60% to about 90%. In one embodiment, the methods produce aμ-opioid receptor occupancy (as measured by a maximum effect model ofEquation 1) of about 65% to about 85%. In one embodiment, the methodsproduce a μ-opioid receptor occupancy (as measured by a maximum effectmodel of Equation 1) of about 65% to about 80%. In one embodiment, themethods produce a μ-opioid receptor occupancy (as measured by a maximumeffect model of Equation 1) of about 65% to about 76%. In oneembodiment, the methods produce a μ-opioid receptor occupancy (asmeasured by a maximum effect model of Equation 1) of about 65% to about75%. In the methods described herein, the μ-opioid receptor occupancy isachieved from one to four months after the first injection, when theinjections are given on a monthly basis. In one embodiment, the μ-opioidreceptor occupancy is achieved from one to three months after the firstinjection, when the injections are given on a monthly basis. In oneembodiment, the μ-opioid receptor occupancy is achieved from one to twomonths after the first injection, when the injections are given on amonthly basis. In one embodiment, the μ-opioid receptor occupancy isachieved within two months after the first injection, when theinjections are given on a monthly basis. In one embodiment, the μ-opioidreceptor occupancy is achieved within one month after the firstinjection, when the injections are given on a monthly basis.

In one embodiment, the disclosure provides methods of treating opioiddependence or pain in a human in need thereof comprising the steps of(a) administering a first composition of Formulation A, B, C, or Dcomprising buprenorphine to the human once per month by injection forone month; and thereafter (b) administering a second composition ofFormulation A, B, C, or D comprising buprenorphine to the human once permonth by injection beginning with the second month of administration andfor each month thereafter; to treat the opioid dependence or pain;wherein the amount of buprenorphine in the first composition is greaterthan the amount of buprenorphine in the second composition. In oneembodiment, the first and second compositions are Formulation A. In oneembodiment, the first and second compositions are Formulation B. In oneembodiment, the first and second compositions are Formulation C. In oneembodiment, the first and second compositions are Formulation D. In oneembodiment, the first composition comprises from about 25 mg to about500 mg buprenorphine, and the second composition comprises from about 1mg to about 400 mg buprenorphine; provided that the amount ofbuprenorphine in the first composition is greater than the amount ofbuprenorphine in the second composition. In another embodiment, thefirst composition comprises from about 150 mg to about 500 mgbuprenorphine, and the second composition comprises from about 10 mg toabout 250 mg buprenorphine; provided that the amount of buprenorphine inthe first composition is greater than the amount of buprenorphine in thesecond composition. In another embodiment, the first compositioncomprises from 176 mg to about 500 mg buprenorphine, and the secondcomposition comprises from about 10 mg to 175 mg buprenorphine. Inanother embodiment, the first composition comprises from about 200 mg toabout 400 mg buprenorphine, and the second composition comprises fromabout 25 mg to about 160 mg buprenorphine. In another embodiment, thefirst composition comprises from about 250 mg to about 350 mgbuprenorphine, and the second composition comprises from about 50 mg toabout 150 mg buprenorphine. In another embodiment, the first compositioncomprises from about 280 mg to about 320 mg buprenorphine, and thesecond composition comprises from about 80 mg to about 120 mgbuprenorphine. In another embodiment, the first composition comprisesabout 300 mg buprenorphine, and the second composition comprises about100 mg buprenorphine. In one embodiment, one month is 28 days. In oneembodiment, one month is 30 days. In one embodiment, one month is 31days. In one embodiment, the injection is a subcutaneous injection.

In one embodiment, the disclosure provides methods of treating opioiddependence or pain in a human in need thereof comprising the steps of(a) administering a first composition of Formulation A, B, C, or Dcomprising buprenorphine to the human once per month by injection fortwo months; and thereafter (b) administering a second composition ofFormulation A, B, C, or D comprising buprenorphine to the human once permonth by injection beginning with the third month of administration andfor each month thereafter; to treat the opioid dependence or pain;wherein the amount of buprenorphine in the first composition is greaterthan the amount of buprenorphine in the second composition. In oneembodiment, the first and second compositions are Formulation D. In oneembodiment, the first composition comprises from about 25 mg to about500 mg buprenorphine, and the second composition comprises from about 1mg to about 400 mg buprenorphine; provided that the amount ofbuprenorphine in the first composition is greater than the amount ofbuprenorphine in the second composition. In another embodiment, thefirst composition comprises from about 150 mg to about 500 mgbuprenorphine, and the second composition comprises from about 10 mg toabout 250 mg buprenorphine; provided that the amount of buprenorphine inthe first composition is greater than the amount of buprenorphine in thesecond composition. In another embodiment, the first compositioncomprises from 176 mg to about 500 mg buprenorphine, and the secondcomposition comprises from about 10 mg to 175 mg buprenorphine. Inanother embodiment, the first composition comprises from about 200 mg toabout 400 mg buprenorphine, and the second composition comprises fromabout 25 mg to about 160 mg buprenorphine. In another embodiment, thefirst composition comprises from about 250 mg to about 350 mgbuprenorphine, and the second composition comprises from about 50 mg toabout 150 mg buprenorphine. In another embodiment, the first compositioncomprises from about 280 mg to about 320 mg buprenorphine, and thesecond composition comprises from about 80 mg to about 120 mgbuprenorphine. In another embodiment, the first composition comprisesabout 300 mg buprenorphine, and the second composition comprises about100 mg buprenorphine. In one embodiment, one month is 28 days. In oneembodiment, one month is 30 days. In one embodiment, one month is 31days. In one embodiment, the injection is a subcutaneous injection.

In one embodiment, the disclosure provides methods of treating opioiddependence or pain in a human in need thereof comprising the steps of(a) administering a first composition of Formulation A, B, C, or Dcomprising buprenorphine to the human once per month by injection forthree months; and thereafter (b) administering a second composition ofFormulation A, B, C, or D comprising buprenorphine to the human once permonth by injection beginning with the fourth month of administration andfor each month thereafter; to treat the opioid dependence or pain;wherein the amount of buprenorphine in the first composition is greaterthan the amount of buprenorphine in the second composition. In oneembodiment, the first and second compositions are Formulation D. In oneembodiment, the first composition comprises from about 25 mg to about500 mg buprenorphine, and the second composition comprises from about 1mg to about 400 mg buprenorphine; provided that the amount ofbuprenorphine in the first composition is greater than the amount ofbuprenorphine in the second composition. In another embodiment, thefirst composition comprises from about 150 mg to about 500 mgbuprenorphine, and the second composition comprises from about 10 mg toabout 250 mg buprenorphine; provided that the amount of buprenorphine inthe first composition is greater than the amount of buprenorphine in thesecond composition. In another embodiment, the first compositioncomprises from 176 mg to about 500 mg buprenorphine, and the secondcomposition comprises from about 10 mg to 175 mg buprenorphine. Inanother embodiment, the first composition comprises from about 200 mg toabout 400 mg buprenorphine, and the second composition comprises fromabout 25 mg to about 160 mg buprenorphine. In another embodiment, thefirst composition comprises from about 250 mg to about 350 mgbuprenorphine, and the second composition comprises from about 50 mg toabout 150 mg buprenorphine. In another embodiment, the first compositioncomprises from about 280 mg to about 320 mg buprenorphine, and thesecond composition comprises from about 80 mg to about 120 mgbuprenorphine. In another embodiment, the first composition comprisesabout 300 mg buprenorphine, and the second composition comprises about100 mg buprenorphine. In one embodiment, one month is 28 days. In oneembodiment, one month is 30 days. In one embodiment, one month is 31days. In one embodiment, the injection is a subcutaneous injection.

In one embodiment, the disclosure provides methods of treating opioiddependence or pain in a human in need thereof comprising the steps of(a) administering a first composition of Formulation A, B, C, or Dcomprising buprenorphine to the human once per month by injection forfour months; and thereafter (b) administering a second composition ofFormulation A, B, C, or D comprising buprenorphine to the human once permonth by injection beginning with the fifth month of administration andfor each month thereafter; to treat the opioid dependence or pain;wherein the amount of buprenorphine in the first composition is greaterthan the amount of buprenorphine in the second composition. In oneembodiment, the first and second compositions are Formulation D. In oneembodiment, the first composition comprises from about 25 mg to about500 mg buprenorphine, and the second composition comprises from about 1mg to about 400 mg buprenorphine; provided that the amount ofbuprenorphine in the first composition is greater than the amount ofbuprenorphine in the second composition. In another embodiment, thefirst composition comprises from about 150 mg to about 500 mgbuprenorphine, and the second composition comprises from about 10 mg toabout 250 mg buprenorphine; provided that the amount of buprenorphine inthe first composition is greater than the amount of buprenorphine in thesecond composition. In another embodiment, the first compositioncomprises from 176 mg to about 500 mg buprenorphine, and the secondcomposition comprises from about 10 mg to 175 mg buprenorphine. Inanother embodiment, the first composition comprises from about 200 mg toabout 400 mg buprenorphine, and the second composition comprises fromabout 25 mg to about 160 mg buprenorphine. In another embodiment, thefirst composition comprises from about 250 mg to about 350 mgbuprenorphine, and the second composition comprises from about 50 mg toabout 150 mg buprenorphine. In another embodiment, the first compositioncomprises from about 280 mg to about 320 mg buprenorphine, and thesecond composition comprises from about 80 mg to about 120 mgbuprenorphine. In another embodiment, the first composition comprisesabout 300 mg buprenorphine, and the second composition comprises about100 mg buprenorphine. In one embodiment, one month is 28 days. In oneembodiment, one month is 30 days. In one embodiment, one month is 31days. In one embodiment, the injection is a subcutaneous injection.

The disclosure provides dosing regimens for treating opioid dependenceor pain in a human in need thereof including the steps of: (a)administering a first composition including a dose of buprenorphine tothe human once per month by injection for one month, two months, orthree months; and thereafter (b) administering a second compositionincluding a dose of buprenorphine to the human once per month byinjection beginning with the second month, third month, or fourth monthof administration, respectively, and for each month thereafter; to treatthe opioid dependence or pain; wherein the amount of buprenorphine inthe first composition is greater than the amount of buprenorphine in thesecond composition. In embodiments, the dosing regimen is for treatingopioid dependence. In embodiments, the dosing regimen is for treatingpain. In embodiments, the first and second compositions comprise (i)buprenorphine in the form of a free base or a pharmaceuticallyacceptable salt; (ii) ethanol or N-methyl-2-pyrrolidone; (iii) a neutraldiacyl lipid and/or a tocopherol; and (iv) a phospholipid. In oneembodiment, the first and second compositions comprise (i) buprenorphinein the form of a free base or a pharmaceutically acceptable salt; (ii)30 to 90% of a lipid matrix comprising at least one monoglyceride, atleast one diglyceride, at least one triglyceride, at least onephospholipid, at least one tocopherol, or mixtures thereof; and (iii) 2%to 35% by weight an organic solvent selected from ethanol, propyleneglycol, N-methyl-2-pyrrolidone, DMSO, and mixtures thereof. Inembodiments, the first and second compositions comprise (i)buprenorphine in the form of a free base or a pharmaceuticallyacceptable salt; (ii) 30% to 90% by weight of at least one neutraldiacyl lipid comprising diacyl glycerols and containing at least 50% ofa glycerol dioleate; (iii) 10% to 60% by weight of at least onephospholipid having polar head groups consisting of at least 50%phosphatidylcholine; and (iv) 2-30% by weight of ethanol,N-methyl-2-pyrrolidone, or a combination thereof. Such compositions aredescribed in U.S. Pat. No. 8,892,782 and US Publication No.2013/0190341, the disclosures of which are incorporated by referenceherein in their entirety.

The sustained-release buprenorphine formulation includes a flowablecomposition and an implant. The sustained-release buprenorphineformulation provides an in situ sustained release of buprenorphine. Theflowable composition accomplishes the sustained release by producing theimplant in situ. The implant has a low volume and provides a long term,therapeutic delivery of buprenorphine. The flowable composition enablessubcutaneous formation of the implant in situ and causes little or notissue necrosis.

Methods for making the sustained-release buprenorphine formulationsdescribed herein are known in the art and described, for example, inU.S. Pat. Nos. 8,921,387 and 8,975,270, the disclosures of which areincorporated by reference herein in their entirety. In particular, theflowable composition is produced by combining all of the componentsrecited in each of Formulas A, B, C, and D. The flowable composition canbe administered by a syringe and needle to a patient in need oftreatment. Other buprenorphine formulations that may be used in themethods described herein can be prepared by other methods known in theart, such as those described in US Publication No. 2013/210853, USPublication No. 2013/0202658, and WO 2014/016428, the disclosure ofwhich are incorporated by reference herein in their entirety.

EXAMPLES

The following examples are for illustrative purposes and are notintended to limit the scope of the disclosure.

Example 1

Formulation D (containing 200 mg/mL buprenorphine base in a formsuitable for subcutaneous injection and allowing for the release ofbuprenorphine at therapeutic levels for at least 28 days) was used.Following administration of Formulation D, day-to-day compliance overthe ensuing month would not be a potential issue as it is with existingproducts that are administered on a daily basis. Also, since FormulationD contains buprenorphine base in a sustained release deliveryformulation, the safety profile and clinical efficacy of Formulation Dare expected to be similar to that of sublingually administeredbuprenorphine (e.g., SUBUTEX®) and buprenorphine/naloxone treatments(e.g., SUBOXONE®).

The primary goal of this study was to develop a model-based approach torationally support and justify the dose and dosing regimen ofFormulation D in Phase 2 and 3 trials. For this purpose, a modelingstrategy was implemented to characterize the population pharmacokineticsof buprenorphine and norbuprenorphine (major metabolite ofbuprenorphine), and to assess the relationship between buprenorphine andμORO. In addition, the relationship between plasma concentration, μORO,withdrawal symptoms and attenuation (i.e., blockade) of hydromorphonechallenge agonist effects was explored. Trial simulations were used forpredicting the expected μORO after repeated subcutaneous injections ofdifferent doses of Formulation D administered once monthly. Themodel-based approach aimed at determining the Formulation D dosage rangethat is expected to sustain a μORO level of 70% and to establish thecorresponding levels of withdrawal symptoms suppression and blockade ofthe effects of exogenously administered opioids.

The study was a single-center, open-label, sequential cohort, singleascending-dose study. Thirty-six opioid-dependent (by Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Text Revisioncriteria) subjects were randomized to receive Formulation D containing50 mg buprenorphine, 100 mg buprenorphine, or 200 mg buprenorphine.Subjects in each cohort received a single subcutaneous dose ofFormulation D on Day 1. On Day 1, blood samples for measuring plasmaconcentrations were drawn at 0.5, 1, 2, 4, 6, 8 and 12 hour post-dose,daily on Day 2 through Day 22, and on Days 25, 28, 31, 35, 42, 49, 56,63, 70, 77, 84, 112, 140, and 150. Human ethylenediaminetetraacetic acid(EDTA) treated plasma samples were analyzed for buprenorphine andnorbuprenorphine using a validated liquid chromatography coupled totandem mass spectrometry (LC-MS/MS) method. Human plasma containingbuprenorphine, norbuprenorphine, and the internal standards,buprenorphine-D4 and norbuprenorphine-D3, was extracted with an organicsolvent mixture after the addition of sodium hydroxide solution(liquid-liquid extraction). After extraction, the extract wasevaporated, reconstituted, and an aliquot was injected on a Sciex API5000 LC-MS/MS equipped with an UPLC column. Quantitation was performedusing separate weighted (1/x2 for buprenorphine and 1/x fornorbuprenorphine) linear least squares regression analyses generatedfrom fortified plasma calibration standards prepared immediately priorto each run. The method was validated for specificity, linearity, lowerlimit of quantitation, precision, accuracy, recovery and stability for arange of 0.0250 to 5.0 ng/mL for buprenorphine and 0.0200 to 4.00 ng/mLfor norbuprenorphine based on the analysis of 0.500 mL of plasma. Theoverall precision for both analytes was better than 6.3%; the overallaccuracy was within ±10.3%. The recoveries for both analytes andinternal standards were above 80%. The established short-term andlong-term stability covered the maximum sample storage time (methodsunpublished).

All data preparation, summary statistics (mean, median, standarddeviation, and other measures, as appropriate), logistic regressionanalysis, report and graphical display presentation were performed usingR (version 2.14.1) (Foundation for Statistical Computing (2009). R: alanguage and environment for statistical computing website:www.R-project.org. Accessed 14 Dec. 2013). The populationpharmacokinetic analysis was conducted using the NONMEM software,Version 7.2 (Beal et al, NONMEM user's guide, 1989-2013. Ellicott City:Icon Development Solutions; 2013). NONMEM was run in a Windows Vistaoperating system using the Fortran compiler gfortran version 4.6.0.Diagnostic graphics, exploratory analyses and post-processing of NONMEMoutputs were performed using R and Xpose (version 4.3) (Parke et al,Comput Meth Prog Bio., 59:19-29 (1999)). The Perl based softwarePerl-speaks-NONMEM (PsN) (version 3.4.2) was used to performbootstrapping and visual predictive checks (VPCs) (Kobayashi et al, DrugMetab Disp., 26:818-21 (1998)).

The first-order conditional estimation with interaction method (FOCE-I)was used for estimating the fixed and random effect parameters using anon-linear-mixed effect approach. Appropriateness of the model wasevaluated using various goodness-of-fit criteria, including diagnosticscatter plots, likelihood-ratio-test (LRT), and measures of modelstability and adequacy (successful convergence, significant digits,matrix singularity). The results for LRT were considered statisticallysignificant if decreases in the objective function value (OFV) of nestedmodels were more than 3.84 (P<0.05, 1 degree of freedom) throughout themodel building process.

The inter-individual variability (IIV) on all the model parameters wasassumed log-normally distributed. The residual variability, which wascomprised of, but not limited to intra-individual variability,experimental errors, process noise and/or model misspecifications, wasmodeled using additive, proportional, and combined error structures.

An outlier was defined as an aberrant observation that significantlydeviates from the rest of observations in a particular individual anddid not refer to a subject as an outlier. The proportion of outliers ina dataset should be low and such points may be excluded from theanalysis given the potential for these observations to negatively impactthe convergence and/or parameter estimates (i.e., which may cause abias) (Food and Drug Administration Guidance for Industry: PopulationPharmacokinetics (1999)). Outlier detection was based initially onvisual examination of individual and pooled pharmacokinetic profiles.Additionally, data points identified with an absolute conditionalweighted residual (|CWRES|)>3 during the initial model building processwere excluded from the analysis. The CWRES are weighted residualscalculated using the FOCE method and have been shown to represent areliable estimate of the distribution of residuals (Hooker et al, PharmRes, 24(12):2187-2197 (2007)). Given the theoretical distribution ofCWRES, it is expected that 99.73% of the CWRES should lie in theinterval −3, 3; for this reason, values outside this interval wereconsidered as outliers.

Buprenorphine is metabolized primarily by cytochrome P450 3A4 tonorbuprenorphine. Buprenorphine undergoes extensive first pass in theliver, thus it is administered sublingually with 50% to 60%bioavailability. The population pharmacokinetic model was developed todescribe simultaneously the concentrations of buprenorphine andnorbuprenorphine.

Age, sex, race, and dose were considered in the covariate analysis.Covariate model building was a step-wise process consisting of a forwardand a backward selection procedure. The LRT was used to evaluate thesignificance of incorporating or removing fixed effects in thepopulation model based on alpha levels that were set a priori.Initially, each covariate was individually included in the base model. Acovariate was retained in the model if a reduction in the objectivefunction value (OFV) was ≥3.84 (χ²<0.05). After defining the full model,the significance of each covariate was tested individually by removingeach one from the full model. A covariate was retained in the model if,upon removal, the OFV increased by more than 6.64 points (χ²<0.001).

A non-parametric bootstrap resampling method was used to evaluate thestability and robustness of the final pharmacokinetic model (Parke etal, Comput Meth Prog Biomed, 59:19-29 (1999)). Resampling withreplacement generated 100 bootstrap data sets and the final populationpharmacokinetic model was fitted repeatedly to each of the 100 bootstrapdata sets. The median and 95% confidence intervals of parametersobtained from this step were compared with the final parameterestimates. In addition, a VPC was also performed. Results from the VPCwere assessed using graphical comparison of the appropriate 90%prediction intervals from simulated data with overlaid observed datafrom the original dataset.

It is recognized that the medication assisted treatment of opioiddependence is related to the opioid pharmacotherapy occupying brainμ-opioid receptors. The level of receptor occupancy is expected tomediate the abuse and dependence potential of opioids and to predictclinical efficacy. Specifically, higher medication doses arehypothesized to decrease μ-opioid receptor availability (or “bindingpotential”) and provide agonist replacement that minimizes withdrawalsymptoms and prevents the reinforcing, euphoric, and other effects ofabused opioids resulting greater clinic attendance (Greenwald et al,Neuropsychopharmacology, 28:2000-2009 (2003). Opioid withdrawal symptomsare the body's physical response to the absence of the opioid, whichinclude muscle aches, restless anxiety, diarrhea, abdominal cramping,nausea and vomiting. In clinical trials, subjective opioid withdrawalscales are used to quantify these withdrawal effects. In addition, theblockade of hydromorphone challenge agonist effects is measured bysubjective drug-effect assessments which often employ ratings on visualanalog scales using adjectives that reflect abuse potential such as“liking” or “good effect”. These measures are quantitative and exhibitdose-response sensitivity to opioid exposure.

The experimental individual values for buprenorphine plasmaconcentrations, μORO, opioid withdrawal syndrome, and opioid-likeagonist effects were provided from two published clinical trials. Intrial 1, 5 heroin-dependent subjects underwent buprenorphine inductionfrom 4 mg/day on Day 1 to 16 mg/day by Day 7 and were maintained at 32mg/day for 12 days. On the 8^(th) day of the maintenance period,subjects were challenged with the opioid agonist hydromorphone andsubjective drug effects were ascertained, and on Day 9, blood samplesfor the measurement of buprenorphine and norbuprenorphine were collectedfollowing buprenorphine administration. On the 10^(th) and 11^(th) dayof the maintenance period, opioid withdrawal symptoms were measuredprior to buprenorphine administration and 1, 2, 3, 6, and 12 hoursafterwards. On the 12^(th) and final day of the maintenance period, apositron emission tomography (PET) scan with [¹¹C]-carfentanil wasadministered 4 hours after buprenorphine administration to measure μORO.Subjects were titrated down to the subsequent maintenance periods atbuprenorphine doses of 16 mg/day for 12 days, 2 mg/day for 12 days, andto 0 mg/day for 12 days. During each subsequent maintenance periodsubjects underwent the hydromorphone challenge, measurement of opioidwithdrawal symptoms, and a PET scan (Greenwald et al,Neuropsychopharmacology, 28:2000-2009 (2003)).

In trial 2, 10 heroin-dependent subjects were initially maintained ≥2weeks on 16 mg/day buprenorphine given as sublingual tablets. Plasmabuprenorphine concentration, opioid withdrawal symptoms, and fourhydromorphone challenges (to measure subjective opioid agonist drugeffects) or four PET brain scans with [¹¹C]-carfentanil (to measureμORO) were conducted at 4, 28, 52, and 76 hours after the last dailybuprenorphine dose. In addition to characterizing the relationshipbetween buprenorphine plasma concentration and μORO, the study assessedthe relationship between μORO and two key clinical effects—opioidwithdrawal syndrome and blockade of hydromorphone agonist subjectivedrug effects (Greenwald et al, Biol Psychiatry, 61:101-110 (2007).

In both trials, opioid agonist and withdrawal symptoms were assessed byusing an Opioid Symptom Questionnaire with 16 agonist and 16 withdrawalscale items. Each item was scored from 0 (not at all) to 4 (extremely),yielding total scores ranging from 0 to 64. Buprenorphine attenuation(blockade) of hydromorphone agonist effects was measured by six visualanalog scales (VAS) ratings including: any drug effect, high, good drugeffect, bad drug effect, stimulated, and sedated (Greenwald et al,Neuropsychopharmacology, 28:2000-2009 (2003); Greenwald et al, BiolPsychiatry, 61:101-110 (2007). From both trials, whole brain imagingresults were used to calculate receptor μOR availability. Percent μOROwas calculated as (100 minus μ-opioid receptor availability).

The analysis dataset included 36 subjects for a total of 2797observations with 66 observations below the lower limit ofquantification. These values were considered as missing in the NONMEManalysis. The buprenorphine and norbuprenorphine measurements weresimultaneously fitted using the ADVAN5 TRANS1 routine in NONMEM. Theabsorption of Formulation D from the subcutaneous injection site wasdescribed by a dual model that was described by a first-order absorptionprocess associated with the rapid absorption and the first observedpeak; and a delayed delivery process that was described by a transitcompartment absorption model to mimic the sustained-release componentsof Formulation D (Savic et al, J Pharmacokinet Pharmacodyn, 34:711-726(2007). The disposition model was a one-compartment model with afirst-order elimination, and first-order conversion to norbuprenorphine.This metabolite was subsequently distributed in a peripheral compartmentand eliminated according to a first-order process.

Initial analysis of the distribution of the CWRES indicated that 28observations showed an absolute CWRES>3. These values satisfied thedefinition of outlier measurements. Therefore, a new dataset wasgenerated where these measurements were considered as missingobservations.

The new analysis dataset included 36 subjects for a total of 2,769observations. The buprenorphine and norbuprenorphine concentrations wereagain simultaneously fitted using the ADVAN5 TRANS1 routine in NONMEM.The residual error model included a combined additive (Add Err) andproportional components with a different proportional component forbuprenorphine (Prop Err BUP) and for norbuprenorphine (Prop Err NorBUP).The results of this analysis were considered as the final model.

Overall, there was no apparent bias in the goodness-of-fit diagnosticplots and in the evaluation of the VPCs, suggesting that the finalpopulation pharmacokinetic model was adequate in describing thebuprenorphine and norbuprenorphine plasma concentration-time courses atFormulation D doses of 50 mg buprenorphine, 100 mg buprenorphine, and200 mg buprenorphine.

The high level of agreement between the parameter estimated by NONMEMand by the bootstrap procedure, together with the precision of theestimated parameters, supports the adequacy of the model to describethese data.

Empirical Bayesian estimates of individual parameters and random effectswere obtained from the base model in the NONMEM analysis. Therelationships between individual model parameters and the selectedcovariates were evaluated graphically. Inspection of the generated plotsindicated a potential impact of sex on the volume of distribution forthe central norbuprenorphine compartment V₃. This hypothesis wasformally tested by incorporating sex as covariate of V₃ in the model.However, the resulting objective function did not show a significantchange with respect to the base model. Overall, it was not possible toidentify any covariate with significant impact on the populationpharmacokinetic variability, given the relatively small number ofsubjects in the study.

A saturable E_(max) model with an additive error model was used fordescribing the relationship between buprenorphine plasma concentrationsand μORO as shown in Equation 1:

$\begin{matrix}{{\mu\;{ORO}} = \frac{E_{{ma}\; x} \cdot {Cp}}{{EC}_{50} + {Cp}}} & \left( {{Equation}\mspace{14mu} 1} \right)\end{matrix}$where Cp is buprenorphine plasma concentration and EC₅₀ is buprenorphineplasma concentration expected to achieve 50% of the maximal μORO(E_(max)). This model was developed assuming a direct relationshipbetween plasma concentration and μORO without equilibration delay. Thismodel assumes that the metabolite norbuprenorphine has negligibleactivity with respect to brain μORO. The analysis dataset (μORO andbuprenorphine pharmacokinetic sampling) included 15 subjects with atotal of 59 pharmacokinetic/μORO data. The modeling was performed usingthe FOCE-I method as implemented in the NONMEM software.

The estimated value for E_(max) (standard error) was 91.4% (3.94) andthe estimated value for EC₅₀ (standard error) was 0.67 (0.19) (ng/mL).The inter-individual variability of E_(max) was not estimated due to thelimited number of measures available in the proximity of the estimatedE_(max) value. The adequacy of the final model was evaluated using thevisual predictive check method. Four-hundred replicates of the originaldataset were simulated based on the final model, and a 90% predictioninterval was computed based on the simulated datasets. The observed μOROversus the buprenorphine concentration data were plotted on theprediction interval to visually assess the concordance between thesimulated and observed data. Statistics of interest including the medianwere calculated from the simulated and observed data for comparison. Themedian population prediction and distributions of quantiles (5th,median, 95th) of simulated data were compared and found to be bestdescribed by a linear relationship between μORO and buprenorphine plasmaconcentrations up to 2 ng/mL. When buprenorphine levels approached 2-3ng/mL, the μORO was saturated and reached a plateau with occupancyranging between 70-90%. Greenwald et al, Biol Psychiatry, 61:101-110(2007) suggests that the threshold for suppressing withdrawal and theblockade of agonist symptom effects is between 50-60% buprenorphine μOROwhile additional benefit and clinical efficacy was observed at 70% μORO.As a result of these findings, a 70% μORO was the desired target. Thepredictive checks seems to indicate a larger variability in modelpredictions compared to observations at the saturation levels (e.g.,above 3-4 ng/mL concentrations), and more data would be required tovalidate the model predictions for that concentration range.

Regression models were used to describe relationships between meanhydromorphone induced changes in agonist symptoms, mean withdrawalsymptom scores, or mean buprenorphine plasma concentrations each withrespect to the mean μ-opioid receptor availability. These data suggestthat at a mean buprenorphine plasma concentration of 2 ng/mL is able toprovide the desired 70% μ-opioid receptor occupancy. The same conditionsare associated with low reported agonist drug effects and withdrawalsymptoms (scores ≤2). For the treatment of opioid dependence, thepositive clinical outcomes are free of withdrawal, cravings and thedrug-induced highs and lows of addiction. The individuals who exhibitgreater μORO and more suppression of withdrawal symptoms experiencebetter treatment outcomes (Greenwald et al, Imaging opioid receptors:applications to substance use disorders. In: Dean et al, editors. Opioidreceptors and antagonists: from bench to clinic. New York: Humana Press,pages 45-65 (2009)). As buprenorphine plasma concentrations decline,there is a concomitant increase in subjective hydromorphone agonist drugeffects and withdrawal symptoms with a corresponding decrease inμ-opioid receptor occupancy.

The simulated drug concentrations of buprenorphine and norbuprenorphineafter repeated subcutaneous injections of Formulation D were derivedfrom the final model parameter estimates. The 400 hypothetical subjectsreceived 4 subcutaneous injections of Formulation D containing 50 mg,100 mg buprenorphine, 200 mg buprenorphine, or 300 mg buprenorphinedoses separated by 28 days. The objective of this simulation was topredict buprenorphine plasma concentrations after multiple doses ofFormulation D and to consequently predict the corresponding μORO.Simulation indicated that the desired >70% receptor occupancy may beachieved after multiple doses of Formulation D containing 200 mgbuprenorphine.

Example 2

This study implemented pharmacokinetic/pharmacodynamics (PK/PD) modelingto support the clinical development of Formulation D, asustained-release formulation of buprenorphine for the treatment ofopioid dependence. Such a formulation could offer advantages overexisting buprenorphine pharmacotherapy by improving patient complianceand reducing the diversion of the product.

A population pharmacokinetic model was developed using 36opioid-dependent subjects who received single subcutaneous doses ofFormulation D. Another PK/PD model was developed using μ-opioid receptoroccupancy data to predict efficacy of Formulation D after repeateddoses. It was also assessed how buprenorphine plasma concentrations werecorrelated to opioid withdrawal symptoms and hydromorphone agonistblockade data from 15 heroin-dependent subjects.

The resulting pharmacokinetic model accurately described buprenorphineand norbuprenorphine plasma concentrations. A saturable maximum effect(E_(max)) model with 0.67 ng/mL effective concentration at 50% ofmaximum (EC₅₀) and 91% E_(max) best described μORO versus buprenorphineplasma concentrations. Linear relationships were found among μORO,withdrawal symptoms, and blockade of agonist effects.

Previous published findings demonstrate μORO≥70% is needed to achievewithdrawal suppression and blockade of opioid agonist subjectiveeffects. Model simulations indicated that Formulation D containing 200mg buprenorphine should achieve 2-3 ng/mL buprenorphine averageconcentrations and desired efficacy.

This study demonstrated the relationship among buprenorphine plasmaconcentrations, μORO, and blockade of opioid agonist effects. Asaturable E_(max) model was established between buprenorphine plasmalevels and μORO. The desired buprenorphine activity was achieved atμORO≥70%. A buprenorphine plasma concentration of 2 ng/mL is required toachieve a μORO of approximately 70%. This analysis provided new insightonto the long-acting pharmacokinetic and pharmacokinetic/μORO profile ofFormulation D.

Example 3

As described in Examples 1 and 2, modeling showed that mu opioidreceptor occupancy (RO)≥70% and buprenorphine plasma levels ≥2 ng/mL areneeded to provide full blockade of opioid agonist effects (Nasser et al,Clin Pharmacokinet, 2014). This example was performed to assessFormulation D (containing 300 mg buprenorphine) blockade ofhydromorphone-induced subjective and reinforcing effects, and todetermine the accuracy of the modeling presented in Example A in aclinical setting.

A total of 39 subjects with moderate or severe opioid use disorder (notseeking treatment) first completed 3 hydromorphone challenges (0, 6, 18mg intramuscular on 3 consecutive days in randomized order), then 3hydromorphone challenges at the end of 14-day SUBOXONE® filmstabilization. This was followed by two injections of Formulation D(containing 300 mg buprenorphine) separated by 28 days. For 12 weeksafter the first Formulation D dose, on days 5-7 of each week, subjectsreceived 3 hydromorphone challenges in randomized (6 sequences) order. ADrug Liking visual analog scale (VAS) score was the primary, andhydromorphone reinforcing effects (log breakpoint values), and VAS forAny Effect, Bad Effect, High, Good Effect, and Sedation were secondaryendpoints. Statistical comparison using mixed effects model was used foreach week. Change from hydromorphone 0 mg with 95% CI was reported, witha difference cut-off of less than or equal to 11 was required to declarefull blockade. A PK sample was collected the morning of eachhydromorphone administration day. The E_(max) model of Equation 1 wasused to calculate μ-opioid receptor occupancy.

For Drug Liking, mean differences for 6 or 18 mg hydromorphone comparedto placebo were <7 units on week 1 and decreased over the 12 weeks.After the second Formulation D injection, the 95% CI of the differenceincluded 0. Hydromorphone reinforcing effects and all VAS showed similarresults. Buprenorphine concentrations were 1.8-3.7 ng/mL and theμ-opioid receptor occupancy was 65-76% over the 12 weeks.

At 300 mg of buprenorphine, Formulation D blocked hydromorphonesubjective and reinforcing effects from weeks 1-12 in patients withmoderate or severe opioid use disorder.

Example 4

Data were obtained from an open label, multiple dose study conducted in89 treatment-seeking opioid-dependent subjects. Subjects were inductedand stabilized on SUBUTEX® (buprenorphine, Indivior UK Limited) atvarious doses (8-24 mg) before transitioning to Formulation D (50, 100,200, or 300 mg) given as 4 subcutaneous monthly injections. A jointpopulation PK model was developed from buprenorphine plasmaconcentrations measured after SUBUTEX® (buprenorphine, Indivior UKLimited) and treatment with Formulation D. Model simulations wereconducted to assist dose selection and evaluate the impact of drugholidays. Prediction of μ-opioid receptors occupancy (μORO) was based ona previously developed PK/PD model (Nasser et al, Clin Pharmacokinet,2014).

Modeling and simulation showed that a 300 mg dose of Formulation D every28 days was appropriate for immediately achieving an effective exposureafter the first SC injection and could maintain effective levels ofexposure during chronic treatment. Furthermore, simulations indicatedthat in the unexpected event of two-week holiday the levels of μOROremained consistently above 80% with no significant loss of drugefficacy. The results of the analysis provided quantitative criteria foreffective clinical dose selection and showed that a two-week drugholiday did not result in a loss of drug efficacy.

Example 5

A 6 month clinical study will be conducted to test two different dosageregimens of Formulation D on patients seeking treatment for opioiddependence. Patient Group 1 will be administered a 300 mg dose ofbuprenorphine base of Formulation D on Month 1 (day 1) and Month 2 (day29), and will then be administered a 100 mg dose of buprenorphine baseof Formulation D on Month 3 (day 57), Month 4 (day 85), Month 5 (day113), and Month 6 (day 141). Patient Group 2 will be administered a 300mg dose of buprenorphine base of Formulation D on each of Months 1, 2,3, 4, 5, and 6. The pk/pD modeling analysis predicts that the averagebuprenorphine concentration (C_(ave) in ng/mL) for each month for eachgroup will be as follows:

TABLE 1 Schedules for dosing regimen Month 1 Month 2 Month 3 Month 4Month 5 Month 6 Patient Group 1 1.9 3.1 3.0 3.0 2.8 2.6 Patient Group 21.9 3.1 4.3 5.1 5.7 6.0

Study Design: This was an open-label, multiple dose study (NLMIdentifier: NCT01738503). This study enrolled 89 treatment-seekingopioid-dependent subjects based on criteria from the Diagnostic andStatistical Manual of Mental Disorders, 4th Edition, Text Revision(DSM-IV-TR). Subjects were inducted and stabilized (over a 13-dayperiod) on SUBUTEX® (buprenorphine sublingual tablet; Indivior,Richmond, Va.) at doses of 8 mg, 12 mg, 14 mg, 24 mg, or 8-24 mg toreceive Formulation D containing doses of 50 mg, 100 mg, or 200 mgbuprenorphine in 4 subcutaneous (SC) injections separated by 28 days or300 mg buprenorphine in 6 subcutaneous (SC) injections separated by 28days. The 6 cohorts were defined as follows (the first dose is SUBUTEX®and the second dose is Formulation D): Cohort #1 (n=15) 8 mg+50 mg;Cohort #2 (n=15) 12 mg+100 mg; Cohort #3 (n=15) 24 mg+200 mg; Cohort #4(n=15) 8 mg+100 mg; Cohort #5 (n=15) 14 mg+200 mg, and Cohort #6 (n=14)8-24 mg+300 mg.

Blood Collection Schedule: Blood samples for buprenorphine PKassessments were collected during the SUBUTEX® stabilization period atpre-dose time on Day −7 to Day-1 then at 0.5, 1, 2, 4, 6, 8, 12, and 24hours post-dose on Day-1. After the first Formulation D subcutaneousinjection, blood samples were collected at 1, 2, 4, 6, 8, 12, 20, 24,30, 48, 144, 192, 240, 312, 384, 456, 528, and 600 hours post-dose.During the second, third and fifth (300 mg dose) Formulation Dsubcutaneous injections, blood samples were collected at: pre-dose, 1,12, 24, 48, 192, 312, and 456 hours post-dose. During the fourthFormulation D subcutaneous injection or the sixth Formulation D SCinjection (300 mg dose only), blood samples were collected at: pre dose,1, 2, 4, 6, 8, 12, 20, 24, 30, 48, 144, 192, 240, 312, 384, 456, 528,600, 672, 864, 1008, 1200, and 1344 hours post-dose. The plasma sampleswere analyzed using a validated method of a liquid chromatography withtandem mass spectrometry (LC-MS/MS) for buprenorphine. The LLOQ forbuprenorphine was 50 pg/mL.

Population pharmacokinetic analysis: A population PK model was developedto simultaneously describe the time course of the buprenorphine plasmaconcentrations after repeated doses of SUBUTEX® during the induction andstabilization period and the repeated SC injections of Formulation D.Circulating buprenorphine concentrations were calculated as theresultant of SUBUTEX® and Formulation D administrations. A total of 5498observations obtained in 89 subjects were included in the population PKanalysis.

Previously published models were selected as a starting point for modelbuilding. Nasser et al, Clin. Pharmacokinet, 53(9):813-824 (2014). Thechoice of the final models was based on the analysis of thesemi-logarithmic scatter plots of the buprenorphine plasmaconcentrations versus time. After SUBUTEX® administration, thebuprenorphine PK profile was best described by a two-compartment modelwith a first-order absorption rate constant (k12), a distribution in theperipheral compartment (rate constants k23 and k32) and a first-orderelimination rate constant (k20).

After SC administration, Formulation D exhibited complex kinetics ofbuprenorphine with a prolonged plasma terminal half-life. The resultingPK time course suggested that the likely model accounted for a dualabsorption process: the first one associated with a rapid delivery fromthe SC injection site (first-order absorption process) and the secondone associated with the slow delivery from Formulation D (delayeddelivery process described by a transit compartment absorption model8).In this model, ka1 is the first-order absorption rate constantcharacterizing buprenorphine immediately reaching the systemiccirculation, ka2 is the first-order absorption rate constantcharacterizing the rate of buprenorphine entering into the transitcompartment system, kk1 is the rate characterizing the delayed processin the transit compartments, k50 is the elimination rate constant ofbuprenorphine, and k56 and k65 are the transfer rate constants betweenthe central and peripheral buprenorphine compartments. In this model S2represents the volume of distribution of the central compartment forbuprenorphine after SUBUTEX® administration and S5 represents the volumeof distribution of buprenorphine after SC administration of FormulationD.

The buprenorphine plasma concentrations were modeled using the ADVAN6routine in NONMEM software version 7.3. The stochastic approximationexpectation-maximization (SAEM) with interaction computational algorithmwas used for estimation of population PK model parameters. The maximumnumber of iterations in the stochastic phase (NBURN) of the SAEM methodwas 2000 followed by 500 iterations in the accumulation phase (NITER).Convergence was assessed visually based on SAEM convergence plots forthe fixed and random effect parameters. The −2 log-likelihood (−2LL)value at the final model parameter estimates was calculated using theimportance sampling approach (IMP) as implemented in NONMEM version 7.3.

Model selection was based on various goodness-of fit criteria, includingstandard diagnostic plots, likelihood-ratio-test (LRT), and visualpredictive checks (VPC). The results for LRT were consideredstatistically significant if decreases in −2LL of nested models weremore than 3.84 (p<0.05, one degree of freedom) throughout the modelbuilding process. The inter-individual variability (IIV) was modeledassuming a log-normal distribution for individual PK parameters. Therelationship between a PK parameter (P) and the subject-specific randomeffect was expressed as:P _(j) =P _(TV) e ^(ηpj)  (Equation 2)where Pj is the value of the PK parameter for the jth individual, P_(TV)is the typical value of P in the population, and ηpj denotes thedifference between Pj and P_(TV). The random effects ηpj were assumed tobe independent and identically distributed with a mean of zero andvariance of ωp².

The residual variability, which comprised of, but was not limited tointra-individual variability, experimental errors, process noise and/ormodel misspecifications, was modeled using additive, proportional, andcombined error structures. The “combined additive and proportionalerror” was retained in the final model.

Covariate Analysis. The following variables: age, BMI, Weight, Gender,Race, Ethnicity were prospectively identified as potential covariates.Covariate model building was a step-wise process consisting of a forwardand a backward selection procedure. The LRT was used to evaluate thesignificance of incorporating or removing fixed effects into thepopulation model based on alpha levels that were set a priori.Initially, each covariate was individually included in the base model. Acovariate was retained into the model if a reduction in −2LL was ≥3.84(χ²<0.05). After the full model was defined, the significance of eachcovariate was tested individually by removing each one at the time fromthe full model. A covariate was retained in the model if, upon removal,the −2LL increased by more than 6.64 points (χ²<0.001).

Model Evaluation. Visual predictive checks (VPC) with 200 simulateddatasets were used to assess the predictive performance of the model.Results from the VPC were assessed by graphical comparison of themedians and appropriate 90% prediction intervals calculated at each timepoint from the simulated data compared to observed data from theoriginal dataset.

Assess clinical effective dose and evaluate the impact of missed doseson Formulation D PK and μORO. The level of μORO is recognized as one ofthe drivers of the clinical efficacy of buprenorphine. The currentlyaccepted hypothesis is that the μORO should be greater than 70% toachieve optimal opioid blockade in the treatment of opioid use disorder.In a previous study, a population PK/μORO model was developed to fullycharacterize the relationship between buprenorphine plasma levels andμORO. Nasser et al, Clin. Pharmacokinet, 53(9):813-824 (2014). Thisrelationship was best described by an Emax model with an EC50 of 0.67ng/mL and an Emax of 91%. The rational for clinical dose selection ofFormulation D was based on the evaluation of the dose appropriate forproviding the target receptor occupancy. Furthermore, the dose selectioncriterion was also explored in the event a patient occasionally fails totake the prescribed dose at the prescribed time. For this purpose,additional simulations were conducted to evaluate the impact of themissed doses on Formulation D on the predicted μORO for repeated dosesof 100 mg or 300 mg. For each dose level (100 mg or 300 mg), threescenarios were explored: Scenario 0: Reference scenario where a subjecttakes the dose at the prescribed time (once every 4 weeks); Scenario 1:1 SC injection of Formulation D, with 2-week holiday prior to the 2nd SCinjection of Formulation D; Scenario 2: 3 SC injections of Formulation Dgiven at a 28-day interval, with 2-week holiday prior to the 4th SCinjection of Formulation D.

For all scenarios, predictions of buprenorphine plasma concentrationsand μORO were generated using the present population PK model andpreviously published PK/μORO model Greenwald et al,Neuropsychopharmacology, 28:2000-2009 (2003).

Software. All data preparation was performed using R (version 3.0.2).The population PK analysis was conducted using the NONMEM software,version 7.3. NONMEM was run in a Windows 8.1 operating system using theFortran compiler gfortran version 4.6.0. Diagnostic graphics,exploratory analyses and post-processing of NONMEM outputs wereperformed using R and Xpose (version 4.3).

Subjects Characteristics. A total of 89 subjects were included in theanalysis. The mean age was 33.8 year, mean weight was 72.5 kg and themean BMI was 24.6 (mg/kg2). There were 26 females and 60 males in thestudy. The majority of the subjects were White (70%) with only 30% beingBlack or African American.

Final Population PK Model. Age was found to significantly affect k12 andBMI was found to significantly affect ka2. The covariate models used forAGE and BMI were:k ₁₂=θ_(k12) ·e ^((−Age·θ) ^(Age) ⁾  (Equation 3)k _(a2)−0_(ka2) ·e ^((−(BMI-24.64)·θ) ^(BMI) ⁾  (Equation 4)where 24.64 represents the mean value of BMI in the study.

Overall, there was no apparent bias in the goodness-of-fit plots,suggesting that the final population PK model was adequate in describingthe buprenorphine plasma concentration-time course.

The adequacy of the final model was evaluated using the VPC method.Two-hundred replicates of the original dataset were simulated based onthe final population PK model, and the distribution of the simulateddata was summarized at each time point by the median and 90% predictioninterval (delineated by the 5th and 95th percentiles). The concordancebetween the observations and the simulated data (medians and 90%prediction intervals) was assessed graphically following normalizationby the dose in order to present all the data on a same plot.

The VPC method for the SUBUTEX® pre-treatment and for Formulation Dtreatment show that the overall population PK model analyzing thebuprenorphine time-course after the SUBUTEX® induction period and afterthe repeated SC injections of Formulation D performed well. Also, thevariability in the data was well described by the model, althoughslightly overestimated for Formulation D. Altogether, thegoodness-of-fit plots and VPC indicated that the population PK modelproperly described the observed data.

Dose selection and Impact of missed doses of Formulation D. Predictedtime-courses of μORO for repeated SC injections of Formulation D at 50mg, 100 mg, 200 mg and 300 mg reveal that a μORO greater than 70% wouldbe achieved just after the first dose of 300 mg of Formulation D. Thislevel is then maintained during chronic treatment. The target μORO levelcan also be reached with the dose of 200 mg. However, at this dose, theexpected μORO will not reach the effective level during the first monthof treatment. Altogether, these findings support the choice of 300 mg asa starting dose for treatment of opioid dependence.

The results of the simulations conducted for evaluating the potentialimpact of drug holiday found that in the case of repeated doses of 300mg, the predicted levels of μORO after two-week holiday remainedconsistently above 80%, suggesting that the probability of lackingefficacy with Formulation D under these circumstances is extremely low.

The objective of this analysis was to develop a model-based approach tocharacterize the population PK of buprenorphine after multiple SCinjections of 50 mg, 100 mg, 200 mg and 300 mg doses of Formulation D intreatment seeking opioid-dependent subjects who were inducted and thenstabilized on a buprenorphine sublingual tablet (SUBUTEX®) dose of 8 mg,12 mg, 14 mg or 24 mg prior to transfer. The secondary objective was todefine the rationale for clinical dose selection and to evaluate theimpact of missed doses on the expected level of Formulation D efficacy.

The analysis of the PK profile of buprenorphine after Formulation Dadministration revealed a complex and multi-phase absorption profile,with sustained buprenorphine plasma concentrations over the dosinginterval. These distinguishing features of the PK of buprenorphinerequired the development of a complex PK model accounting for thisabsorption processes associated with Formulation D into the systemiccirculation.

The mean transit time (defined as the number of transitcompartments/kk1) associated with the slow release of buprenorphine fromFormulation D could be estimated at ˜5.5 weeks, which is the likelyreason for the curvilinear shape of the plasma concentration-timeprofile. The results of the analysis confirmed earlier predictions ofbuprenorphine plasma exposures after repeated SC injections ofFormulation D at the doses of 50 mg to 300 mg previously generated usingsingle dose PK data. Nasser et al, Clin. Pharmacokinet, 53(9):813-824(2014).

The model outcomes indicated that a linear and time invariant PK modelis appropriate for characterizing the PK of buprenorphine and forpredicting the exposure expected at different dosage regimens. Thecovariates analysis provided important insight into the absorptionprocess of buprenorphine. BMI was identified as a statisticallysignificant covariate affecting the absorption process of Formulation D.Patients with smaller BMI showed a higher rate of the absorption processassociated with buprenorphine delivery from Formulation D (ka2).However, the rate of the immediate absorption (ka1) was not affected bythe BMI. For this reason the Cmax value of buprenorphine remainedsubstantially invariant with respect to the BMI values. The absorptionprocess of the sublingual administration of SUBUTEX® was found to beaffected by age. The rate of absorption from the sublingual site to thesystemic circulation (k12) decreased with the increase of age.

It is recognized that the efficacy of a buprenorphine treatment foropioid dependence is associated with μORO. In Greenwald et al,Neuropsychopharmacology, 28:2000-2009 (2003), a population PK/μORO modelwas developed using buprenorphine PK and μORO data collected in 15heroin-dependent subjects (5 subjects receiving buprenorphine dailytablet doses of 32 mg, 16 mg or 2 mg, or placebo, and 10 subjectsreceiving a buprenorphine daily tablet dose of 16 mg). This studycharacterized the relationship between buprenorphine plasmaconcentrations, μORO and blockade of opioid agonist effects. A saturablemaximum effect (Emax) model was established between buprenorphine plasmalevels and μORO. This model showed a linear relationship between μORO upto the desired 70% receptor occupancy and buprenorphine concentrationsup to approximately 2 ng/mL. At buprenorphine concentrations greaterthan 2 ng/mL, saturation occurred on μORO where a 4.5-fold increase inobserved buprenorphine concentrations resulted in observed μORO between70% and less than 90%. Thus, once μORO is saturated, increasing dosesare not expected to exert any appreciable effect. A linear correlationwas established between buprenorphine clinical efficacy (withdrawalsuppression and blockade of hydromorphone agonist subjective effects)and μORO.

This previous PK/μORO model [Nasser et al, Clin. Pharmacokinet,53(9):813-824 (2014)] together with the present population PK model wereused to conduct simulations and predict μORO after repeated SCinjections of Formulation D containing buprenorphine at doses of 50 mg,100 mg, 200 mg and 300 mg. The results of the simulations providedquantitative criteria for the clinical dose selection for the late phaseclinical development of Formulation D: the dose of 300 mg every 28 dayswas found to be appropriate for immediately achieving an effectiveexposure after the first SC injection and to maintain an effective levelof exposure during chronic treatment. Furthermore, the results of thesimulations conducted to evaluate the potential impact of holiday indrug intake indicated that in the unexpected event of one- or two-weekholiday the level of μORO remained consistently above 80% for repeateddoses of 300 mg. This finding indicates that significant loss ofFormulation D efficacy may not be expected under these unexpectedcircumstances.

Embodiments

Embodiment 1. A method of treating opioid dependence or pain in a humanin need thereof including the steps of: (a) administering a firstcomposition including a dose of buprenorphine to the human once permonth by injection for one month, two months, or three months; andthereafter (b) administering a second composition including a dose ofbuprenorphine to the human once per month by injection beginning withthe second month, third month, or fourth month of administration,respectively, and for each month thereafter; to treat the opioiddependence or pain; wherein the amount of buprenorphine in the firstcomposition is greater than the amount of buprenorphine in the secondcomposition.

Embodiment 2. The method of Embodiment 1, wherein the first compositionis administered to the human once per month for one month, and thesecond composition is administered to the human once per month beginningwith the second month.

Embodiment 3. The method of Embodiment 1, wherein the first compositionis administered to the human once per month for two months, and thesecond composition is administered to the human once per month beginningwith the third month.

Embodiment 4. The method of Embodiment 1, wherein the first compositionis administered to the human once per month for three months, and thesecond composition is administered to the human once per month beginningwith the fourth month.

Embodiment 5. The method of Embodiment 1, wherein the first compositioncomprises from about 150 mg to about 500 mg buprenorphine, and thesecond composition comprises from about 10 mg to about 250 mgbuprenorphine; and wherein the amount of buprenorphine in the firstcomposition is greater than the amount of buprenorphine in the secondcomposition.

Embodiment 6. The method of Embodiment 1, wherein the first compositioncomprises from 176 mg to about 500 mg buprenorphine, and the secondcomposition comprises from about 10 mg to 175 mg buprenorphine.

Embodiment 7. The method of Embodiment 1, wherein the first compositioncomprises from about 200 mg to about 400 mg buprenorphine, and thesecond composition comprises from about 25 mg to 160 mg buprenorphine.

Embodiment 8. The method of Embodiment 1, wherein the first compositioncomprises from about 250 mg to about 350 mg buprenorphine, and thesecond composition comprises from about 50 mg to 150 mg buprenorphine.

Embodiment 9. The method of Embodiment 1, wherein the first compositioncomprises from about 280 mg to about 320 mg buprenorphine, and thesecond composition comprises from about 80 mg to 120 mg buprenorphine.

Embodiment 10. The method of Embodiment 1, wherein the first compositioncomprises about 300 mg buprenorphine, and the second compositioncomprises about 100 mg buprenorphine.

Embodiment 11. The method of any of Embodiments 1 to 10, wherein thebuprenorphine is in the form of a free base.

Embodiment 12. The method of any of Embodiments 1 to 10, wherein thebuprenorphine is in the form of a pharmaceutically acceptable salt.

Embodiment 13. The method of any one of Embodiments 1 to 12, wherein themethod produces an average buprenorphine concentration of about 0.5ng/mL to about 5 ng/mL in the human.

Embodiment 14. The method of any one of Embodiments 1 to 12, wherein themethod produces an average buprenorphine concentration of about 1 ng/mLto about 4.5 ng/mL in the human.

Embodiment 15. The method of any one of Embodiments 1 to 12, wherein themethod produces an average buprenorphine concentration of about 1.5ng/mL to about 4 ng/mL in the human.

Embodiment 16. The method of any one of Embodiments 1 to 12, wherein themethod produces an average buprenorphine concentration of about 1.5ng/mL to about 3.5 ng/mL in the human.

Embodiment 17. The method of any one of Embodiments 1 to 12, wherein themethod produces an average buprenorphine concentration of about 2 ng/mLto about 3 ng/mL in the human.

Embodiment 18. The method of any one of Embodiments 1 to 12, wherein themethod produces an average buprenorphine concentration of about 2 ng/mLto about 4 ng/mL in the human.

Embodiment 19. The method of any one of Embodiments 1 to 12, wherein themethod produces an average buprenorphine concentration of about 3 ng/mLto about 4 ng/mL in the human.

Embodiment 20. The method of any one of Embodiments 1 to 12, wherein themethod produces an average buprenorphine concentration of about 1.8ng/mL to about 3.7 ng/mL in the human.

Embodiment 21. The method of any one of Embodiments 13 to 20, whereinthe average buprenorphine concentration is achieved from one to fourmonths after the first injection.

Embodiment 22. The method of any one of Embodiments 13 to 20, whereinthe average buprenorphine concentration is achieved from one to threemonths after the first injection.

Embodiment 23. The method of any one of Embodiments 13 to 20, whereinthe average buprenorphine concentration is achieved from one to twomonths after the first injection.

Embodiment 24. The method of any one of Embodiments 13 to 20, whereinthe average buprenorphine concentration is achieved within two monthsafter the first injection.

Embodiment 25. The method of any one of Embodiments 13 to 20, whereinthe average buprenorphine concentration is achieved within one monthafter the first injection.

Embodiment 26. The method of any one of Embodiments 1 to 13, wherein themethod produces a μ-opioid receptor occupancy (as measured by a maximumeffect model of Equation 1) greater than 60% in the human.

Embodiment 27. The method of any one of Embodiments 1 to 13, wherein themethod produces a μ-opioid receptor occupancy (as measured by a maximumeffect model of Equation 1) of at least 70%.

Embodiment 28. The method of any one of Embodiments 1 to 13, wherein themethod produces a μ-opioid receptor occupancy (as measured by a maximumeffect model of Equation 1) of greater than 60% to about 90%.

Embodiment 29. The method of any one of Embodiments 1 to 13, wherein themethod produces a μ-opioid receptor occupancy (as measured by a maximumeffect model of Equation 1) of about 65% to about 85%.

Embodiment 30. The method of any one of Embodiments 1 to 13, wherein themethod produces a μ-opioid receptor occupancy (as measured by a maximumeffect model of Equation 1) of about 65% to about 80%.

Embodiment 31. The method of any one of Embodiments 1 to 13, wherein themethod produces a μ-opioid receptor occupancy (as measured by a maximumeffect model of Equation 1) of about 65% to about 76%.

Embodiment 32. The method of any one of Embodiments 1 to 13, wherein themethod produces a μ-opioid receptor occupancy (as measured by a maximumeffect model of Equation 1) of about 65% to about 75%.

Embodiment 33. The method of any one of Embodiments 26 to 32, whereinthe μ-opioid receptor occupancy is achieved from one to four monthsafter the first injection.

Embodiment 34. The method of any one of Embodiments 26 to 32, whereinthe μ-opioid receptor occupancy is achieved from one to three monthsafter the first injection.

Embodiment 35. The method of any one of Embodiments 26 to 32, whereinthe μ-opioid receptor occupancy is achieved from one to two months afterthe first injection.

Embodiment 36. The method of any one of Embodiments 26 to 32, whereinthe μ-opioid receptor occupancy is achieved within two months after thefirst injection.

Embodiment 37. The method of any one of Embodiments 26 to 32, whereinthe μ-opioid receptor occupancy is achieved within one month after thefirst injection.

Embodiment 38. The method of any one of Embodiments 1 to 37, wherein theinjection is a subcutaneous injection.

Embodiment 39. The method of any one of Embodiments 1 to 38, wherein amonth is from 28 days to 31 days.

Embodiment 40. The method of any one of Embodiments 1 to 38, wherein amonth is 28 days.

Embodiment 41. The method of any one of Embodiments 1 to 40 for treatingopioid dependence in the human in need thereof.

Embodiment 42. The method of Embodiment 41, wherein the method oftreating opioid dependence is a method of suppressing opioid withdrawalsigns and symptoms.

Embodiment 43. The method of any one of Embodiments 1 to 40 for treatingpain in the human in need thereof.

Embodiment 44. The method of any one of Embodiments 1 to 10, wherein thefirst composition and the second composition each comprises, consistsessentially of, or consists of: (i) about 18 wt % buprenorphine in theform of the free base; (ii) about 32 wt % of a 50:50poly(DL-lactide-co-glycolide) copolymer having an average molecularweight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about50 wt % of N-methyl-2-pyrrolidone.

Embodiment 45. The method of any one of Embodiments 1 to 10, wherein thefirst composition and the second composition each comprises, consistsessentially of, or consists of: (i) about 14 wt % to about 22 wt %buprenorphine in the form of the free base; (ii) about 22 wt % to about42 wt % of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymerhaving an average molecular weight of about 5,000 Daltons to about30,000 Daltons; and (iii) about 40 wt % to about 60 wt % ofN-methyl-2-pyrrolidone.

Embodiment 46. The method of any one of Embodiments 1 to 10, wherein thefirst composition and the second composition each comprises, consistsessentially of, or consists of: (i) about 10 wt % to about 30 wt %buprenorphine in the form of the free base; (ii) about 10 wt % to about60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymerhaving an average molecular weight of about 5,000 Daltons to about40,000 Daltons; and (iii) about 30 wt % to about 70 wt % ofN-methyl-2-pyrrolidone.

Embodiment 47. The method of any one of Embodiments 1 to 10, wherein thefirst composition and the second composition each includes, consistsessentially of, or consists of: (i) at least one biodegradablethermoplastic polymer; (ii) at least one organic liquid which comprisesan amide, an ester, a carbonate, a ketone, a lactam, an ether, asulfonyl, or a combination thereof; and (iii) buprenorphine in the formof a free base or pharmaceutically acceptable salt.

Embodiment 48. The method of Embodiment 47, wherein the buprenorphine inthe form of a free base or pharmaceutically acceptable salt is presentin the first composition and/or the second composition in an amountbetween about 5 wt % to about 30 wt % or in an amount between about 10wt % and about 25 wt %.

Embodiment 49. The method of Embodiment 47, wherein the buprenorphine inthe form of a free base or pharmaceutically acceptable salt is presentin the first composition and/or the second composition in an amountbetween about 15 wt % and about 20 wt %.

Embodiment 50. The method of Embodiment 47, wherein the organic liquidis present in the first composition and/or the second composition in anamount of about 30 wt % to about 70 wt %.

Embodiment 51. The method of Embodiment 47, wherein the organic liquidis present in the first composition and/or the second composition in anamount of about 40 wt % to about 60 wt %.

Embodiment 52. The method of Embodiment 47, wherein the organic liquidis N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethyleneglycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethylisosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate,monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerolformal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol,dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylenecarbonate, triacetin, dimethylsulfoxide, dimethylsulfone,epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of twoor more thereof.

Embodiment 53. The method of Embodiment 47, wherein the organic liquidis N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide,dimethyl sulfoxide, propylene carbonate, caprolactam, polyethyleneglycol, ethanol, or a mixture of two or more thereof.

Embodiment 54. The method of Embodiment 47, wherein the organic liquidis N-methyl-2-pyrrolidone.

Embodiment 55. The method of Embodiment 47, wherein the biodegradablethermoplastic polymer is present in the first composition and/or thesecond composition in an amount of about 10 wt % to about 60 wt %.

Embodiment 56. The method of Embodiment 47, wherein the biodegradablethermoplastic polymer is present in the first composition and/or thesecond composition in an amount of about 20 wt % to about 40 wt %.

Embodiment 57. The method of Embodiment 47, wherein the polymer is apolylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, aterpolymer thereof, any combination thereof, or a mixture of two or morethereof.

Embodiment 58. The method of Embodiment 47, wherein the polymer is apoly(DL-lactide-co-glycolide) copolymer.

Embodiment 59. The method of Embodiment 47, wherein the polymer has anaverage molecular weight of about 5,000 Daltons to about 40,000 Daltons.

Embodiment 60. The method of Embodiment 47, wherein the polymer has anaverage molecular weight of about 5,000 Daltons to about 30,000 Daltons.

Embodiment 61. The method of Embodiment 47, wherein the polymer has anaverage molecular weight of about 5,000 Daltons to about 20,000 Daltons.

Embodiment 62. The method of Embodiment 47, wherein the polymer has anaverage molecular weight of about 10,000 Daltons to about 20,000Daltons.

Embodiment 63. The method of Embodiment 58, wherein thepoly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5poly(DL-lactide-co-glycolide) copolymer.

Embodiment 64. The method of Embodiment 58, wherein thepoly(DL-lactide-co-glycolide) copolymer is a 50:50 to 80:20poly(DL-lactide-co-glycolide) copolymer.

Embodiment 65. The method of Embodiment 58, wherein thepoly(DL-lactide-co-glycolide) copolymer is a 50:50poly(DL-lactide-co-glycolide) copolymer.

Embodiment 66. The method of Embodiment 58, wherein thepoly(DL-lactide-co-glycolide) copolymer is a 50:50poly(DL-lactide-co-glycolide) copolymer having an average molecularweight from about 5,000 Daltons to about 20,000 Daltons.

Embodiments for practicing the invention have been described. It will beunderstood and readily apparent to the skilled artisan that changes andmodifications may be made to the embodiments described herein withoutdeparting from the spirit and the scope of the invention.

What is claimed is:
 1. A method of treating opioid use disorder in a human in need thereof, the method comprising the steps of: (a) administering a first composition comprising about 300 mg of buprenorphine to the human once per month by subcutaneous injection for two months; wherein the first composition comprises (i) about 18 wt % of buprenorphine free base; (ii) about 32 wt % of a poly(DL-lactide-co-glycolide) copolymer; and (iii) about 50 wt % of N-methyl-2-pyrrolidone; and (b) administering a second composition comprising about 100 mg of buprenorphine to the human once per month by subcutaneous injection beginning with a third month and for at least four months; wherein the second composition comprises (i) about 18 wt % of buprenorphine free base; (ii) about 32 wt % of a poly(DL-lactide-co-glycolide) copolymer; and (iii) about 50 wt % of N-methyl-2-pyrrolidone; to treat the opioid use disorder.
 2. The method of claim 1, wherein the opioid use disorder is moderate opioid use disorder or severe opioid use disorder.
 3. The method of claim 1, wherein the poly(DL-lactide-co-glycolide) copolymer in the first composition and the second composition is a 50:50 poly(DL-lactide-co-glycolide) copolymer.
 4. A method of treating opioid use disorder in a human in need thereof, the method comprising the steps of: (a) administering a first composition comprising about 300 mg of buprenorphine or a pharmaceutically acceptable salt thereof to the human once per month by injection for two months; and (b) administering a second composition comprising about 100 mg of buprenorphine or a pharmaceutically acceptable salt thereof to the human once per month by injection beginning with a third month and for at least four months; to treat the opioid use disorder.
 5. The method of claim 4, wherein the buprenorphine is in the form of a free base.
 6. The method of claim 4, wherein the method produces an average buprenorphine plasma concentration of at least 2 ng/mL.
 7. The method of claim 4, wherein the method produces an average buprenorphine plasma concentration of about 2 ng/mL to about 5 ng/mL.
 8. The method of claim 4, wherein the method produces a μ-opioid receptor occupancy as measured by a maximum effect model of Equation 1 of at least 70%.
 9. The method of claim 4, wherein the injection is a subcutaneous injection.
 10. The method of claim 4, wherein the method of treating opioid use disorder is a method of suppressing opioid withdrawal signs and symptoms.
 11. The method of claim 4, wherein the first composition and the second composition each comprise: (i) about 18 wt % of buprenorphine free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
 12. The method of claim 4, wherein the first composition and the second composition each comprise: (i) about 14 wt % to about 22 wt % of buprenorphine free base; (ii) about 22 wt % to about 42 wt % of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer; and (iii) about 40 wt % to about 60 wt % of N-methyl-2-pyrrolidone.
 13. The method of claim 4, wherein the first composition and the second composition each comprise: (i) about 10 wt % to about 30 wt % of buprenorphine free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
 14. The method of claim 1, wherein the poly(DL-lactide-co-glycolide) copolymer in the first composition and the second composition is a 50:50 poly(DL-lactide-co-glycolide) copolymer having a carboxy terminal group and having an average molecular weight of about 9,000 Daltons to about 19,000 Daltons.
 15. The method of claim 11, wherein the 50:50 poly(DL-lactide-co-glycolide) copolymer has a carboxy terminal group and has an average molecular weight of about 9,000 Daltons to about 19,000 Daltons.
 16. The method of claim 12, wherein the 50:50 to 80:20 poly(DL-lactide-co glycolide) copolymer is a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 30,000 Daltons.
 17. The method of claim 13, wherein the 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons.
 18. The method of claim 4, wherein the opioid use disorder is moderate opioid use disorder or severe opioid use disorder.
 19. The method of claim 1, further comprising transmucosally administering to the patient a composition comprising buprenorphine prior to step (a).
 20. The method of claim 1, further comprising sublingually administering to the patient a composition comprising buprenorphine prior to step (a).
 21. The method of claim 1, further comprising inducting and stabilizing the patient on a transmucosal composition comprising buprenorphine prior to step (a).
 22. The method of claim 1, further comprising inducting and stabilizing the patient on a sublingual composition comprising buprenorphine prior to step (a).
 23. A method of treating opioid addiction in a human in need thereof, the method comprising the steps of: (a) transmucosally administering a composition comprising buprenorphine; (b) subcutaneously administering a first composition comprising about 300 mg of buprenorphine once per month for two months; wherein the first composition comprises (i) about 18 wt % of buprenorphine free base; (ii) about 32 wt % of a poly(DL-lactide-co-glycolide) copolymer; and (iii) about 50 wt % of N-methyl-2-pyrrolidone; and (c) subcutaneously administering a second composition comprising about 100 mg of buprenorphine once per month beginning with a third month and for at least four months; wherein the second composition comprises (i) about 18 wt % of buprenorphine free base; (ii) about 32 wt % of a poly(DL-lactide-co-glycolide) copolymer; and (iii) about 50 wt % of N-methyl-2-pyrrolidone. 